A unique disease known as amyotrophic lateral sclerosis (ALS) and Parkinsonism Dementia Complex (PDC) or ALS/PDC is observed in the Chamorro people of Guam. The clinical features of ALS observed are similar if not identical to ALS observed in other parts of the world. However, Guam ALS is neuropathologically unique in that neurofibfillary tangles, are observed in the cortex and spinal cord, a finding atypical of classical ALS. PDC is Parkinsonism features observed with dementia; again, the neuropathologic features, which are essentially identical to Guam ALS, distinguish PDC from Parkinson's disease. Guam ALS and PDC are considered different clinical manifestations of the same disease. Guam dementia is another disease entity that is clinically indistinguishable from Alzheimer's disease (AD) and may be an additional form of ALS/PDC. Clustering of ALS/PDC in families and a high incidence in specific villages on Guam indicates that genetic factors are important in disease susceptibility. Also, the increase in age-of-onset of ALS and PDC, and the decrease in the incidence of ALS indicate that environmental factors, possibly unique to Guam, are also involved. The goal of this proposal is to identify the genetic susceptibility factors involved in ALS/PDC. Previous work indicated that tau is a susceptibility factor for ALS/PDC but is not the major gene responsible for this group of diseases. This proposal will focus on: 1) identifying additional susceptibility factors for ALS/PDC; 2) identifying the tau alleles the confer susceptibility to ALS/PDC; 3) characterize Guam dementia in terms of genetic markers for AD such as ApoE promoter polymorphisms and ALS/PDC such as tau.